Immunotherapy trials for type 1 diabetes: the contribution of George Eisenbarth.

Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. jskyler@miami.ed

Abstract

Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic β-cells, and as such it should respond to immunotherapy. George Eisenbarth gave many significant contributions to this field. He has been involved at some level in most immunotherapy trials during the past three decades. He was among the pioneers who attempted immunotherapy approaches in patients with recent-onset T1D. In the early 1980s he began studying relatives of those with the disease, leading to the concept that T1D was a chronic autoimmune disease, in which islet autoimmune responses would silently destroy β-cells and cause progressive impairment of insulin secretion, years to months before a diagnosis was made. Consequently, he was one of the first to attempt immune intervention in people at high risk of T1D. Throughout his career he developed autoantibody assays and predictive models (which included metabolic testing and later genetics) to identify individuals at risk of T1D. He provided seminal intellectual contributions and critical tools for prevention trials. His focus on insulin as a critical autoantigen led to multiple prevention trials, including the Diabetes Prevention Trial-Type 1 (DPT-1), which studied both parenteral and oral insulin. In the DPT-1 Oral Insulin Trial, a cohort with higher levels of insulin autoantibodies was identified that appeared to have delayed disease progression. Type 1 Diabetes TrialNet is conducting a new trial to verify or refute this observation. Moreover, George identified and tested in the mouse small molecules that block or modulate presentation of a key insulin peptide and in turn prevent the activation of insulin-specific T-lymphocytes. Thus, we believe his greatest contribution is yet to come, as in the near future we should see this most recent work translate into clinical trials.

Scheme depicting a model of the stages of type 1 diabetes as a chronic progressive autoimmune disease, eventuating in “total” diabetes with absent β-cell function (i.e., no C-peptide production). The x-axis is without a specific time scale as the rate of progress of the disease may be quite variable. Modified from Eisenbarth. (Source: Eisenbarth GS: Autoimmune beta cell insufficiency - diabetes mellitus Type 1. Triangle 1984;23:111–124.)

Updated scheme depicting a model of the stages of type 1 diabetes as a chronic progressive autoimmune disease, with variation in the rate of β-cell destruction during progression to hyperglycemia. Again, the x-axis is without a specific time scale as the rate of progress of the disease may be quite variable. Modified from Eisenbarth. Reprinted from Endocrine Practice, Vol 18, Eisenbarth GS: Prevention of type 1A diabetes mellitus, pp 745–749, 2012, with permission from the American Association of Clinical Endocrinologists.